Many cancers are characterized by disruptions in cellular signaling pathways that lead to aberrant control of cellular processes, or to uncontrolled growth and proliferation of cells. These disruptions are often caused by genetic changes (also called mutations) that affect the activity of particular signaling proteins. A fusion gene is one type of mutation which is a hybrid gene formed from two previously separate genes or from previously non-contiguous regions of the same gene. It can occur, for example, as the result of a translocation, interstitial deletion, or chromosomal inversion.
Among other known examples, tyrosine kinase genes, which encode important enzymes directly regulating cell growth, have been reported to contain oncogenic mutations. Kinase activity can be activated, for example, by substitution or deletion in amino acid sequences and thereby bring about carcinogenesis or contribute to aggressive versus less aggressive cancers, or lead to a propensity for metastasis, or cause drug sensitivity or drug resistance. Although there are many examples, the BCR-ABL gene fusion is one that has long been associated with cancer; in particular, chronic myelogenous leukemia (CML) and in some cases acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL). Other examples include gene rearrangements involving EML4/ALK (e.g., lung cancer), TMPRSS2/ERG (e.g., prostate cancer), IgH/MYC (e.g., Burkitt lymphoma), MYB/NFIB (e.g., carcinomas of the breast and head and neck), TMPRSS2/ETV4 (e.g., prostate cancer), EWSR1/FLI1 (e.g., Ewing sarcoma), and many others known to those of skill in the art or yet to be discovered.
In the context of neoplastic transformation, it is known that some genes are highly promiscuous in that they may recombine with many different partners, for example, within the same tumor entities, e.g., MLL in acute leukemias (Collins and Rabbitts, Trends in Molecular Medicine, 8(9): 436-442 2002), EWSR1 in bone and soft tissue tumors (Helman and Meltzer, Nature Reviews Cancer, 3(9): 685-694, 2003), and RET in thyroid carcinomas (Pierotti, Nature Reviews Cancer, 1(3): 245-250, 2001). However, the same fusion gene may also give rise to tumors of totally different derivations, and one particular fusion gene, ETV6-NTRK3, has been described in cancers as diverse as acute myeloid leukemia, infantile fibrosarcoma, mesoblastic nephroma, and breast carcinoma (Tognon et al., Cancer Cell, 2(5): 367-376, 2002). There are also several examples where seemingly identical chromosomal aberrations produce different fusion genes. One of the most common translocations in pre-B acute lymphoblastic leukemia, t(1;19)(q23;p13) leading to a TCF3/PBX1 fusion, may result in a chimeric transcript consisting of two entirely different genes, MEF2D in 1q23 and DAZAP1 in 19q13 (Yuki et al., Cancer Science, 95 (6):503-507, 2004).
Gene fusions can be diagnostic markers or therapeutic targets, as well as useful for predicting patient prognosis and/or response to drugs. Further, it is clear that multiple fusions may arise in the same tumor or subject and/or that each subject may have medically relevant gene fusions that differ from other afflicted subjects. Accordingly, new technologies for detecting gene fusions are critically important to advance science and medicine.